In this competing renewal of our MERIT Award, the central goal is to further the understanding of the occurrence of asymptomatic amyloid-beta (A?) deposition and its progression to clinical cognitive impairment. During the previous eight years we collected A? imaging and cognitive data on 75 cognitively normal older adults to determine if the variability in cognition in this group was explained largely by A? deposition and found that it was not. This cohort has now matured to the point that the occurrence of incident Mild Cognitive Impairment (MCI) and incident A?-positivity [incident-A?(+)] is sufficient to address other important hypotheses that could not be properly addressed until sufficient follow-up was in place - as is the case now. One critical hypothesis that we can now test is that A?-positive cognitively normal older adults are at high risk to develop clinically-significant cognitive impairment (i.e., MCI) (Aim 1). In addition, our growing cohort of incident-A?(+) subjects allows us to observe the transition from being A?-negative to the earliest A?-positive [A?(+)] state (Aim 2.2). This enables us to measure the time spent A?(+) and avoids many other limitations of cross-sectional studies. Also, our longitudinal fMRI data in incident-A?(+) individuals will allow us to test for the first time the assumption that higher hippocampal activation in A?(+) individuals reflects a true increase from baseline, and not just a maintenance of lifelong high activation as suggested by studies of cerebral metabolism and will aid us in predicting when A?(+) individuals will develop cognitive decline (Aim 3). Finally, we propose to enhance our cohort to more effectively address the relationship between A? deposition and cognition by broadening the cognitive range of our cohort (Aim 2.1). We will do this in an innovative way by adding a group of individuals who do not meet criteria for MCI, but show mild neuropsychological deficits without cognitive or functional complaints. The overall impact and significance of this study will be to further our understanding of: 1) the incidence of asymptomatic ?-amyloidosis; 2) the relationships between early A? deposition, hippocampal activation and cognition; and ultimately, 3) the relationship of asymptomatic ?-amyloidosis and clinical MCI (and the timing of that association). We will continue to employ state-of-the-art neuroimaging methods (including the Pittsburgh Compound-B amyloid imaging technology developed by our group) along with both standard and innovative neurocognitive and clinical measures. Innovative aspects of this project include: 1) the study of incident MCI in A?(+) individuals; 2) the study of incident-A?(+) cases; and 3) the longitudinal study of the natural history of hippocampal activation in incident-A?(+) individuals and its relationship to progression to MCI. Completion of our study will result in a predictive model of MCI that will incorporate the A? and neurodegenerative parameters of the preclinical Alzheimer's disease (AD) criteria. This data will aid in the design and interpretation f existing and ongoing prevention trials for AD and thus have great relevance to the major public health threat posed by this disease.